5-Halo PGI compounds

ABSTRACT

Prostaglandin (PG 1 ) derivatives having (1) a 6-keto feature, for example ##STR1## or (2) a 9-deoxy-6,9-epoxy feature together with a 5-halo or 6-hydroxy feature, for example ##STR2## said derivatives having pharmacological activity. Processes for preparing them and the appropriate intermediates are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a divisional application of Ser. No. 819,857, filed July 28, 1977, now U.S. Pat. No. 4,158,667 issued June 19, 1979; which is a continuation-in-part application of Ser. No. 725,548, filed Sept. 22, 1976, now abandoned; which is a continuation-in-part of Ser. No. 716,972, filed Aug. 23, 1976, now abandoned, which was a continuation-in-part of Ser. No. 655,110, filed Feb. 4, 1976, now abandoned.

The present invention relates to prostaglandin analogs, for which the essential material constituting disclosure therefor is incorporated by reference here from U.S. Pat. No. 4,158,667. 

I claim:
 1. A compound of the formula ##STR3## or a mixture comprising that compound and the enantiomer thereof wherein R₂₁ is ##STR4## wherein R₁₃ is (a) hydrogen, (b) tetrahydropyranyl, (c) tetrahydrofuranyl, (d) 1-ethoxyethyl, (e) a group of the formula ##STR5## wherein R₁₄ is alkyl of one to 18 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, wherein R₁₅ and R₁₆ are the same or different, being hydrogen, alkyl of one to 4 carbon atoms, inclusive, phenyl or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, or, when R₁₅ and R₁₆ are taken together, --(CH₂)a-- or --(CH₂)b--O--(CH₂)c-- wherein a is 3, 4, or 5, b is one, 2, or 3, and c is one, 2, or 3, with the proviso that b plus c is 2, 3, or 4, and wherein R₁₇ is hydrogen or phenyl, or (f) carboxyacyl including ##STR6## wherein "A" is alkyl of one to 4 carbon atoms, inclusive, bromo, phenylalkyl of 7 to 10 carbon atoms, inclusive, or nitro, and "e" is zero to 5, inclusive, provided that not more than two A's are other then alkyl, and that the total number of carbon atoms in the A's does not exceed 10 carbon atoms, ##STR7## wherein R₃₀ is alkyl of one to 4 carbon atoms, inclusive, ##STR8## wherein "A" and "e" are as defined above, or ##STR9## wherein R₃₁ is alkyl of one to 7 carbon atoms, inclusive, wherein L is(1) --(CH₂)d--C(R₂)₂ -- (2) --CH₂ --O--CH₂ --Y-- or (3) --CH₂ CH═CH-- wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being the same or different with the proviso that one R₂ is not methyl when the other is fluoro, and Y is a valence bond, --CH₂ --, or --(CH₂)₂ --,wherein Q is ##STR10## wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and R₁₃ is as defined above, wherein R₁ is (1) --COOR₃ (2) --CH₂ OH (3) --CH₂ N(R₁₉)(R₁₈) ##STR11## wherein R₃ is (a) hydrogen, (b) alkyl of one to 12 carbon atoms, inclusive, (c) cycloalkyl of 3 to 10 carbon atoms, inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl, (f) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, ##STR12## wherein R₁₀ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, and wherein R₁₁ is hydrogen or benzoyl, or (n) a pharmacologically acceptable cation, wherein R₈ is hydrogen, methyl, or ethyl, and wherein R₁₈ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with alkyl of one to 4 carbon atoms, inclusive;wherein R₄ is ##STR13## wherein CgH_(2g) is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ -- and terminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R₅ nor R₆ is fluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--) or CjH_(2j) wherein CjH₂ is a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between CR₅ R₆ -- and the phenyl ring; wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ -- wherein R₇ is alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2, or 3, with the proviso that not more than two T's are other than alkyl and when s is 2 or 3 the T's are either the same or different; wherein R₁₉ is chloro, bromo, or iodo with the proviso that R₁₉ is not bromo when R₂₀ is ##STR14## L is --(CH₂)₃ --, R₄ is n-pentyl, and X is --C.tbd.C--; and wherein X is (1) trans--CH═CH-- (2) cis--CH═CH-- (3) --C.tbd.C-- or (4) --CH₂ CH₂ --.
 2. A compound according to claim 1 wherein R₁₃ is hydrogen.
 3. A compound according to claim 2 wherein R₂₁ is ##STR15##
 4. 5ξ-Iodo-9-deoxy-6ξ,9α-epoxy-11β-PGF₁, methyl ester, compounds according to claim
 3. 5. A compound according to claim 2 wherein R₂₁ is ##STR16##
 6. A compound according to claim 2 wherein R₂₁ is ##STR17##
 7. A compound according to claim 2 wherein R₂₁ is ##STR18##
 8. A compound according to claim 2 wherein R₂₁ is ##STR19##
 9. A compound according to claim 2 wherein R₂₁ is ##STR20##
 10. A compound according to claim 2 wherein R₂₁ is ##STR21## wherein L is ##STR22## n being 3, 4, or 5, wherein Q is or ##STR23## wherein R₈ is limited to hydrogen, methyl, or ethyl, and wherein R₄ is n-pentyl, 1,1-dimethylpentyl, 1,1-difluoropentyl, ##STR24##
 11. A compound according to claim 10 wherein R₁ is ##STR25## wherein R₁₉ and R₁₈ are as defined in claim
 1. 12. 5ξ-Iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, amide, compounds according to claim
 11. 13. 5ξ-Iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, methylamide, compounds according to claim
 11. 14. 5ξ-Iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, n-butylamide, comcpounds according to claim
 11. 15. 5ξ-Iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, benzylamide, compounds according to claim
 11. 16. 5ξ-Iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, anilide, compounds according to claim
 11. 17. A compound according to claim 10 wherein R₁ is --COOR₃ wherein R₃ is as defined in claim
 1. 18. A compound according to claim 17 wherein X is --C.tbd.C--.
 19. 5ξ-Bromo-9-deoxy-6ξ,9α-epoxy-15(R)-13,14-didehydro-PGF₁, methyl ester, compounds according to claim
 2. 20. A compound according to claim 17 wherein X is trans-CH═CH--.
 21. A compound according to claim 20 wherein R₃ is ##STR26## wherein R₁₀ and R₁₁ are as defined in claim
 1. 22. 5ξ-Iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, p-phenylphenacyl ester, compounds according to claim
 21. 23. A compound according to claim 20 wherein R₃ is hydrogen, alkyl of one to 12 carbon atoms, inclusive, or a pharmacologically acceptable cation.
 24. A compound according to claim 23 wherein R₃ is hydrogen, methyl, or a pharmacologically acceptable cation.
 25. 5ξ-Iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, compounds according to claim
 24. 26. 5ξ-Bromo-9-deoxy-6ξ,9α-epoxy-PGF₁, methyl ester, compounds according to claim
 24. 27. 5ξ-Iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, methyl ester, compounds according to claim
 24. 28. 5ξ-Iodo-9-deoxy-6ξ,9.alpha.-epoxy-17-phenyl-18,19,20-trinor-PGF₁, methyl ester, compounds according to claim
 96. 29. A compound according to claim 1 wherein R₁₃ is tetrahydropyranyl.
 30. A compound according to claim 1 wherein R₁₃ is carboxyacyl as defined in claim
 1. 31. 5ξ-Iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, methyl ester, 11,15-bis(4-bromobenzoate), compounds according to claim
 30. 32. A compound according to claim 2 wherein R₄ is ##STR27##
 33. 5ξ-Iodo-9-deoxy-6ξ,9α-epoxy-17,18-didehydro-PGF₁, methyl ester, compounds according to claim
 32. 34. 5ξ-Iodo-9-deoxy-6ξ,9α-epoxy-15-deoxy-PGF₁, methyl ester, compounds according to claim
 24. 35. 5ξ-Iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, p-(p-acetamidobenzamido)-phenyl ester, compounds according to claim
 20. 